Type 2 diabetes is a major health problem in the United States affecting millions of people. It is caused by failure of the pancreatic beta-cells to secrete enough insulin resulting in high blood glucose levels. People with impaired glucose tolerance (IGT) have elevated glucose levels and are at increased risk for progressing to type 2 diabetes. The long-term objectives of this research are to better understand the factors that contribute to the loss of beta-cell function and impaired insulin secretion. High glucose levels have been shown to impair beta- cell function by causing oxidative stress, and oscillating high glucose levels increase oxidative stress even more than continuous high glucose. Diets containing foods with a high glycemic index (GI) increase the glycemic load (GL) of the diet and post-prandial glucose levels. Therefore, high GL (HGL) diets could be potentially damaging to the beta-cell by increasing glucose fluctuations and oxidative stress. Conversely, low GL (LGL) diets may be beneficial. The study explores the hypothesis that increased glycemic variability results in increased oxidative stress and thereby exacerbates beta-cell dysfunction in people with IGT. Specific Aim 1: Determine if a HGL diet worsens and a LGL diet improves beta-cell function compared to a baseline control diet in subjects with IGT. Specific Aim 2: Determine if increased glycemic variability on the HGL diet is associated with decreased beta- cell function and conversely if decreased glycemic variability on the LGL diet is associated with improved beta- cell function in subjects with IGT. Specific Aim 3: Determine if oxidative stress induced by a HGL diet mediates decreases in beta-cell function by determining if 1) systemic markers of oxidative stress are associated with beta-cell function;2) if the relationship between glycemic variability and beta-cell function is at least partially explained by oxidative stress;and 3) the anti-oxidant N-acetylcysteine (NAC) prevents decreases in beta-cell function on a HGL diet. Study design: The study will be a randomized, parallel-design feeding study in men and women with IGT. Subjects will be randomly assigned to one of 3 separate arms (n=15/arm): 1) 4 weeks on a LGL diet (GI<35);2) 4 weeks on a HGL diet (GI>70) + placebo twice daily;or 3) 4 weeks on a HGL diet (GI>70) + NAC 600 mg twice daily. Subjects will be studied after a 2 week baseline control diet with a moderate glycemic load (GI 55- 58) for comparison and all diets will be weight stable with the same macronutrient composition (50% carbohydrate/30% fat/20% protein). Beta-cell function will be assessed by both a frequently sampled intravenous glucose tolerance test and a meal test. Glycemic variability will be assessed by a 3 day Continuous Glucose Monitoring System and glycemic control by fructosamine. Fasting and post-meal plasma nitrotyrosine levels and 24 hour urine isoprostane levels will be measured as markers of oxidative stress. PUBLIC HEALTH RELEVANCE: Understanding whether increased glycemic variability and oxidative stress are important in beta-cell dysfunction is critical for the development of effective strategies aimed at the prevention and treatment of type 2 diabetes. In addition, understanding the contribution of dietary glycemic load to beta-cell dysfunction in subjects with pre-diabetes can have a significant public health impact, including changes to dietary counseling and promotion of healthier eating patterns.